Integrative Regulatory Therapy Research

Chapter 6: Modulating Cellular Signal Transduction

Over the last several decades, molecular biology has gradually been unraveling the way in which the body’s cells work. "Signal transduction" refers to the way in which cellular proteins undergo small and usually reversible alterations in their structure to induce alterations in cell behavior. For example, the catalytic activities of many enzymes are altered through a process known as "phosphorylation". In this process, phosphate groups are attached to specific amino acids – usually serine or tyrosine. The enzymes which attach phosphate groups to proteins are known as "kinases". Their activity is opposed by another group of enzymes, phosphatases", which remove phosphate groups from proteins. Oftentimes, kinases and phosphatases are themselves susceptible to phosphorylations that change their activities (1). Another common way in which the functional properties of cellular proteins are altered is by "oxidation". Oxidant stress can lead to the production of hydrogen peroxide, which can interact with certain cysteine amino acids in proteins to change their functional properties (2,3). These alterations can be reversed by another group of enzymes known as "reductases".

These considerations may sound very abstruse to someone who hasn’t had a chance to study molecular biology, but they have very practical implications for the way cells behave. For example, hormones which bind to cellular receptors often induce these receptors to undergo self-induced phosphorylations of tyrosines in these receptors. This in turn sets off a chain reaction of alterations in the structures of many proteins that can trigger cellular multiplication or migration, and that can make the cells harder to kill with cytotoxic chemotherapy or radiation (4). Moderate levels of intracellular oxidative stress often act to reinforce these changes, by causing temporary inhibition of phosphatases that remove tyrosine phosphate groups.

Cancer cells are distinguished by the fact that, owing to mutagenic alterations in their DNA, or so-called epigenetic (potentially reversible) changes in their DNA structure, the amount of certain proteins made by these cells is increased or decreased, and/or the structure of these proteins is altered in ways that influence their function (5). In cancer, the net impact of these changes is to boost the activity of signal transduction mechanisms that support cellular multiplication, tissue invasion, and metastasis to distant organs, and that protect the cells from being killed by radiation or chemotherapy. Often, cancer cells express increased amounts of cell receptors that phosphorylate tyrosines, or make mutant receptors that are constantly active in this regard (6-8). The pro-growth, pro-survival impacts of these receptors are often amplified by increased oxidant stress in cancer cells, which prevents phosphatase enzymes from turning off the signals triggered by these receptors (9,10).

One of the goals at Oasis of Hope is to use nutrients, phytochemicals, and currently available drugs to suppress signal transduction pathways that are overactive in cancer cells, or boost pathways that are underactive. The intent is for cancer cells grow slower, make them aggressive, or make them easier to destroy.